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WEE1 inhibition triggers GCN2-mediated activation of the integrated stress response

GSE291029 Homo sapiens (human) RNA-seq (gene expression) 12 samples Submitted 2025/10/05 Platform GPL30173
At a glance

RNA-seq (gene expression) · human · 12 samples

What it is
RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism
Homo sapiens (human)
Samples
12 samples: 3 × RPFv4B-WEE11-DMSO vs 3 × RPFv4B-WEE11-WEE1i vs 3 × VASA-WEE11-DMSO vs 3 × VASA-WEE11-WEE1iGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper
WEE1 inhibitors trigger GCN2-mediated activation of the integrated stress responseNature communications · 2025
Summary (written by the submitters)
The WEE1 kinase negatively regulates the CDK1/2 kinases to control DNA replication and prevent premature entry into mitosis. Pharmacological inhibition of WEE1 (WEE1i) causes hyperactivation of CDK1 and CDK2, leading to premature mitosis in the presence of DNA lesions. WEE1i treatment is particularly cytotoxic in cells with oncogene-induced or treatment-induced replication stress.
Read the full summary ↓
To uncover genetic factors that sensitize cancer cells to WEE1i, a genome-wide insertional mutagenesis screen was performed and identified that mutation of the alternative translation initiation factor EIF2A sensitized cells to WEE1i. WEE1i sensitivity of EIF2AKO cells was not explained by altered replication kinetics. Rather, WEE1i leads to a translational shut-down which is lethal in combination with the reduced translation in EIF2AKO cells. A genome-wide CRISPR-Cas9 screen in WEE1i-treated cells revealed that inactivation of the integrated stress response (ISR) kinase GCN2 rescued WEE1i-mediated cytotoxicity. In line with these findings, WEE1i resulted in GCN2 activation, ATF4 upregulation and a translational shutdown. Moreover, WEE1 inhibition leads to altered ribosome dynamics and increased ribosome collisions. Accordingly, cells lacking the collided ribosome sensor ZNF598 show increased sensitivity to WEE1i. This response was not restricted to cancer cells, but was also observed in peripheral blood monocytic cells. The GCN2-mediated ISR was not required for WEE1i to induce DNA damage in S-phase, premature mitotic entry nor the sensitizing effects to DNA damaging chemotherapeutics. Conversely, ISR activation and translational shut-down are independent on WEE1i-mediated activation of CDK1/2. WEE1i-mediated ISR activation was independent of the presence of WEE1, pointing at an off-target effect, which is shared by multiple chemically distinct WEE1 inhibitors. Importantly, WEE1 inhibition at doses that do not induce the ISR can still synergize with PKMYT1 inhibition. Taken together, pharmacological WEE1 inhibition triggers cytotoxic ISR activation and translational shutdown, which can be prevented by low-dose treatments, while retaining the cell cycle checkpoint-perturbing effects.
Published in
WEE1 inhibitors trigger GCN2-mediated activation of the integrated stress response
Tjeerdsma RB, Ng TF, Roorda M et al. · Nature communications 2025 · PMID 41285872 · doi:10.1038/s41467-025-66514-0
This dataset
Open GSE291029 in finder → Find more human RNA-seq datasets →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE291029_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1231422 and SRA study SRP567922. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 41285872) ↗
Study design
3 × RPFv4B-WEE11-DMSO vs 3 × RPFv4B-WEE11-WEE1i vs 3 × VASA-WEE11-DMSO vs 3 × VASA-WEE11-WEE1i

Supports a between-group comparison across 12 samples.

How we read this: 4 replicated groups read from 12 sample titles; they account for 12 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study
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